Our interest in understanding the complex interrelationships between DNA repair, cancer and senescence has led us to study the role of DNA repair in several human model systems which are pertinent to both cancer and aging. We have identified specific fine structure DNA repair phenotypes characteristic of a group of related heritable cancer prone and progeroid human syndromes. We have been able to determine that the tumor suppressor gene p53 most likely plays an active role in the DNA repair process via studies of repair in patients with LiFraumeni syndrome harboring a germ line mutation in p53. By investigating DNA damage induction and repair in progeroid syndromes such as Werner's syndrome, we can examine a human mutant which has several clinical manifestations concordant with normal human aging and also associated with an increased cancer incidence. Alzheimer's disease also provides a useful model system in which to study the role of DNA repair in a condition associated with senescence. We have measured gene-specific repair in fibroblasts from patients with familial and sporadically occurring Alzheimer's disease. Telomeric shortening is one of the age-associated genetic instabilities currently believed to be an important biomarker of aging and cancer. We have developed a novel method to measure DNA damage induction and repair in human telomeres and suspect that repair capacity in telomeres may be related to the genomic instability associated with normal human aging and perhaps with tumorigenesis. These studies are being extended with assays for telomerase activity.